idence of antibodies to other products may be misleading.
Malignancies
During the 6-month, controlled period of the studies, 15 malignancies were diagnosed in patients receiving ACTEMRA, compared to 8 malignancies in patients in the control groups. Exposure-adjusted incidence was similar in the ACTEMRA groups (1.32 events per 100 patient-years) and in the placebo plus DMARD group (1.37 events per 100 patient-years).
In the all-exposure population, the rate of malignancies remained consistent (1.10 events per 100 patient-years) with the rate observed in the 6-month, controlled period [see Warnings and Precautions (5.4)].
Other Adverse Reactions
Adverse reactions occurring in 2% or more of patients on 4 or 8 mg/kg ACTEMRA plus DMARD and at least 1% greater than that observed in patients on placebo plus DMARD are summarized in Table 2.
Table 2 Adverse Reactions Occurring in at Least 2% or More of Patients on 4 or 8 mg/kg ACTEMRA plus DMARD and at Least 1% Greater Than That Observed in Patients on Placebo plus DMARD 6 Month Phase 3 Controlled Study Population
ACTEMRA
8 mg/kg MONOTHERAPY Methotrexate ACTEMRA
4 mg/kg + DMARDs ACTEMRA
8 mg/kg + DMARDs Placebo + DMARDs
Preferred Term N = 288
(%) N = 284
(%) N = 774
(%) N = 1582
(%) N = 1170
(%)
Upper Respiratory Tract Infection 7 5 6 8 6
Nasopharyngitis 7 6 4 6 4
Headache 7 2 6 5 3
Hypertension 6 2 4 4 3
ALT increased 6 4 3 3 1
Dizziness 3 1 2 3 2
Bronchitis 3 2 4 3 3
Rash 2 1 4 3 1
Mouth Ulceration 2 2 1 2 1
Abdominal Pain Upper 2 2 3 3 2
Gastritis 1 2 1 2 1
Transaminase increased 1 5 2 2 1
7 DRUG INTERACTIONS
7.1 Other Drugs for Treatment of Rheumatoid Arthritis
Population pharmacokinetic analyses did not detect any effect of methotrexate, non-steroidal anti-inflammatory drugs or corticosteroids on tocilizumab clearance.
Concomitant administration of a single dose of 10 mg/kg ACTEMRA with 10-25 mg MTX once weekly had no clinically significant effect on MTX exposure.
ACTEMRA has not been studied in combination with biological DMARDs such as TNF antagonists [see Dosage and Administration (2.1)].
7.2 Interactions with CYP450 Substrates
Cytochrome P450s in the liver are down-regulated by infection and inflammation stimuli including cytokines such as IL-6. Inhibition of IL-6 signaling in RA patients treated with tocilizumab may restore CYP450 activities to higher levels than those in the absence of tocilizumab leading to increased metabolism of drugs that are CYP450 substrates. In vitro studies showed that tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Its effects on CYP2C8 or transporters is unknown. In vivo studies with omeprazole, metabolized by CYP2C19 and CYP3A4, and simvastatin, metabolized by CYP3A4, showed up to a 28% and 57% decrease in exposure one week following a single dose of ACTEMRA, respectively. The effect of tocilizumab on CYP enzymes may be clinically relevant for CYP450 substrates with narrow therapeutic index, where the dose is individually adjusted. Upon initiation or discontinuation of ACTEMRA, in patients being treated with these types of medicinal products, therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) should be performed and the individual dose of the medicinal product adjusted as needed. Prescribers should exercise caution when ACTEMRA is coadministered with CYP3A4 substra |
